Novel function of perforin in negatively regulating CD4^＋ T cell activation by affecting calcium signaling

Perforin 是主要从事调停的形成毛孔的蛋白质目标 T 房间死亡并且被细胞毒素的 T 淋巴细胞(CTL ) 和自然漂亮房间采用。然而，它是否也在常规 CD4+ T 房间功能起一个作用，仍然保持不清楚。这里，我们报导那在 perforin 缺乏(PKO ) 老鼠， CD4+ T 房间是响应 T 的 hyperproliferative 房间受体(TCR ) 刺激。hyperproliferation 的这个特征被改进在房间分割并且在 IL-2 分泌物伴随。看起来， perforin 缺乏不在胸腺怒气和淋巴节点影响 T 房间开发。在 vivo， perforin 缺乏导致增加的抗原特定的 T 房间增长和抗体生产。而且， PKO 老鼠更产生试验性的自体免疫的眼色素层炎。探讨分子的机制，我们发现在 TCR 刺激以后，从 PKO 老鼠的 CD4+ T 房间显示增加的细胞内部的钙流动并且随后提高抄写因素 NFAT1 的激活。我们的结果显示 perforin 在由影响 TCR 依赖的 Ca2+ 发信号调整 CD4+ T 房间激活和有免疫力的反应起一个否定作用。

Zoonotic origins of human coronavirus 2019(HCoV-19/SARS-CoV-2):why is this work important?

The ongoing pandemic of coronavirus disease 2019 (COVID-19), caused by infection with human coronavirus 2019 (HCoV-19/SARS-CoV-2/2019-nCoV), is a global threat to the human population. Here, we briefly summarize the available data for the zoonotic origins of HCoV-19, with reference to the other two epidemics of highly virulent coronaviruses, SARSCoV and MERS-CoV, which cause severe pneumonia in humans. We propose to intensify future efforts for tracing the origins of HCoV-19, which is a very important scientific question for the control and prevention of the pandemic.

Treatment of postoperative infectious complications in patients with human immunodef iciency virus infection

BACKGROUND: Antibiotics are widely given for surgical patients to prevent infection. Because of the lack of study on the rational use of antibiotics in patients with human immunodef iciency virus(HIV)-infected during surgical procedures, we analyzed the risk factors affecting postoperative infectious complications in HIV-infected patients and explore the rational use of perioperative antibiotics.METHODS: This retrospective study consisted of 308 HIV-infected patients, 272 males and 36 females, who had undergone operation at the Shanghai Public Health Clinical Center from November 2008 to April 2012. The patients were divided into postoperative infection and non-infection groups. Their age and clinical variables were compared. The correlation between surgical incision, surgical site infection(SSI) and postoperative sepsis was analyzed. Prophylactic antibiotics were used for patients with type I and II incisions for less than 2 days. Patients with type III incisions were given antibiotics until the infection was controlled. Antiretroviral therapy(ART) was prescribed preoperatively for patients whose preoperative CD4 count was <350 cells/μL. For those patients whose preoperative CD4 count was <200 cells/μL, sulfamethoxazole and fluconazole were given preoperatively as prophylactic agents controlling Pneumocystis carinii pneumonia and fungal infection.RESULTS: A total of 196 patients developed postoperative infectious complications, and 7 patients died. Preoperative CD4 counts, ratio of CD4/CD8 cells, hemoglobin level, and postoperative CD4 counts, hemoglobin and albumin levels were risk factors of perioperative infection in HIV-infected patients. Patients with a preoperative CD4 count <200 cell/μL, anemia, a postoperative CD4 count <200 cell/μL or albumin levels <35 g/L were correlated with a higher rate of perioperative infection. There was a signif icant correlation between SSI and the type of surgical incision. The rate of SSI in patients with type I surgical incision was 2% and in those with type II surgical incision was 38%. All the patients who received type III surgical incision developed SSI, and they were more likely to develop postoperative sepsis.CONCLUSIONS: HIV-infected patients are more likely to develop postoperative infectious complications. The rational use of antibiotics in HIV-infected patients could help to reduce the rate of postoperative infectious complications in these patients.

“Unconventional”Neutralizing Activity of Antibodies Against HIV

Neutralizing antibodies are recognized to be one of the essential elements of the adaptive immune response that must be induced by an effective vaccine against HIV. However,only a limited number of antibodies have been identified to neutralize a broad range of primary isolates of HIV-1 and attempts to induce such antibodies by immunization were unsuccessful. The difficulties to generate such antibodies are mainly due to intrinsic properties of HIV-1 envelope spikes,such as high sequence diversity,heavy glycosylation,and inducible and transient nature of certain epitopes. In vitro neutralizing antibodies are identified using "conventional" neutralization assay which uses phytohe-magglutinin (PHA)-stimulated human PBMCs as target cells. Thus,in essence the assay evaluates HIV-1 replication in CD4+ T cells. Recently,several laboratories including us demonstrated that some monoclonal antibodies and HIV-1-specific polyclonal IgG purified from patient sera,although they do not have neutralizing activity when tested by the "conventional" neutralization assay,do exhibit potent and broad neutralizing activity in "unconventional" ways. The neutralizing activity of these antibodies and IgG fractions is acquired through post-translational modifications,through opsonization of virus particles into macrophages and immature dendritic cells (iDCs),or through expression of antibodies on the surface of HIV-1-susceptible cells. This review will focus on recent findings of this area and point out their potential applications in the development of preventive strategies against HIV.

Decoding the complexity of metastasis

Cancer metastasis remains one of the most confounding questions in oncology1,2.Although current cutting-edge techniques enable very early detection of tumors,profiling whether a tumor has already begun to spread and where it has attempted to colonize remains a major hurdle.Indeed,metastatic seeding events exhibit remarkable temporal and spatial heterogeneity,wherein the origin(primary site)and destination(metastatic site)are highly dynamic.For example,liver metastasis is particularly common and remains a leading cause of mortality3.

Prediction of gastric cancer risk by a polygenic risk score of Helicobacter pylori

BACKGROUND Genetic variants of Helicobacter pylori(H. pylori) are involved in gastric cancer occurrence. Single nucleotide polymorphisms(SNPs) of H. pylori that are associated with gastric cancer have been reported. The combined effect of H. pylori SNPs on the risk of gastric cancer remains unclear.AIM To assess the performance of a polygenic risk score(PRS) based on H. pylori SNPs in predicting the risk of gastric cancer.METHODS A total of 15 gastric cancer-associated H. pylori SNPs were selected. The associations between these SNPs and gastric cancer were further validated in 1022 global strains with publicly available genome sequences. The PRS model was established based on the validated SNPs. The performance of the PRS for predicting the risk of gastric cancer was assessed in global strains using quintiles and random forest(RF) methods. The variation in the performance of the PRS among different populations of H. pylori was further examined.RESULTS Analyses of the association between selected SNPs and gastric cancer in the global dataset revealed that the risk allele frequencies of six SNPs were significantly higher in gastric cancer cases than non-gastric cancer cases. The PRS model constructed subsequently with these validated SNPs produced significantly higher scores in gastric cancer. The odds ratio(OR) value for gastric cancer gradually increased from the first to the fifth quintile of PRS, with the fifth quintile having an OR value as high as 9.76(95% confidence interval: 5.84-16.29). The results of RF analyses indicated that the area under the curve(AUC) value for classifying gastric cancer and non-gastric cancer was 0.75, suggesting that the PRS based on H. pylori SNPs was capable of predicting the risk of gastric cancer. Assessing the performance of the PRS among different H. pylori populations demonstrated that it had good predictive power for cancer risk for hp Europe strains, with an AUC value of 0.78.CONCLUSION The PRS model based on H. pylori SNPs had a good performance for assessment of gastric cancer risk. It would be useful in the prediction of final consequences of the H. pylori infection and beneficial for the management of the infection in clinical settings.

BL19U2:Small-angle X-ray scattering beamline for biological macromolecules in solution at SSRF

The BL19U2 at the Shanghai Synchrotron Radiation Facility is a small-angle X-ray scattering beamline dedicated to structural studies pertaining to biological macromolecules in solution.The beamline has been officially opened to users in March 2015,and since then,a series of technological innovations has been developed to optimize beamline performance,thereby significantly improving the data collection efficiency and broadening the application scope of biological small-angle X-ray scattering.BL19U2 is ideal for the high-throughput screening of weakly scattered proteins,protein assemblies,nucleic acids,inorganic nanomaterials,and organic drug molecules.This paper describes the design and overview of the BL19U2 beamline.Versatile sample environments at the experimental station and some recent scientific highlights are presented.

Heteromerization of short-chain trans-prenyltransferase controls precursor allocation within a plastidial terpenoid network

Terpenes are the largest and most diverse class of plant specialized metabolites.Sesterterpenes(C25),which are derived from the plastid methylerythritol phosphate pathway,were recently characterized in plants.In Arabidopsis thaliana,four genes encoding geranylfarnesyl diphosphate synthase(GFPPS)(AtGFPPS1 to 4)are responsible for the production of GFPP,which is the common precursor for sesterterpene biosynthesis.However,the interplay between sesterterpenes and other known terpenes remain elusive.Here,we first provide genetic evidence to demonstrate that GFPPSs are responsible for sesterterpene production in Arabidopsis.Blockage of the sesterterpene pathway at the GFPPS step increased the production of geranylgeranyl diphosphate(GGPP)-derived terpenes.Interestingly,co-expression of sester TPSs in GFPPSOE(overexpression)plants rescued the phenotypic changes of GFPPS-OE plants by restoring the endogenous GGPP.We further demonstrated that,in addition to precursor(DMAPP/IPP)competition by GFPPS and GGPP synthase(GGPPS)in plastids,GFPPS directly decreased the activity of GGPPS through protein-protein interaction,ultimately leading to GGPP deficiency in planta.Our study provides a new regulatory mechanism of the plastidial terpenoid network in plant cells.

Xuebijing alleviates LPS-induced acute lung injury by downregulating pro-inflammatory cytokine production and inhibiting gasdermin-E-mediated pyroptosis of alveolar epithelial cells

Acute lung injury/acute respiratory distress syndrome(ALI/ARDS)is characterized by diffuse alveolar injury primarily caused by an excessive inflammatory response.Regrettably,the lack of effective pharmacotherapy currently available contributes to the high mortality rate in patients with this condition.Xuebijing(XBJ),a traditional Chinese medicine recognized for its potent anti-inflammatory properties,exhibits promise as a potential therapeutic agent for ALI/ARDS.This study aimed to explore the preventive effects of XBJ on ALI and its underlying mechanism.To this end,we established an LPS-induced ALI model and treated ALI mice with XBJ.Our results demonstrated that pre-treatment with XBJ significantly alleviated lung inflammation and increased the survival rate of ALI mice by 37.5%.Moreover,XBJ substantially suppressed the production of TNF-α,IL-6,and IL-1βin the lung tissue.Subsequently,we performed a network pharmacology analysis and identified identified 109 potential target genes of XBJ that were mainly involved in multiple signaling pathways related to programmed cell death and anti-inflammatory responses.Furthermore,we found that XBJ exerted its inhibitory effect on gasdermin-E-mediated pyroptosis of lung cells by suppressing TNF-αproduction.Therefore,this study not only establishes the preventive efficacy of XBJ in ALI but also reveals its role in protecting alveolar epithelial cells against gasdermin-E-mediated pyroptosis by reducing TNF-αrelease.

Soluble CD4 effectively prevents excessive TLR activation of resident macrophages in the onset of sepsis

T lymphopenia,occurring in the early phase of sepsis in response to systemic inflammation,is commonly associated with morbidity and mortality of septic infections.We have previously shown that a sufficient number of T cells is required to constrain Toll-like receptors(TLRs)mediated hyperinflammation.However,the underlying mechanisms remains unsolved.Herein,we unveil that CD4^(+)T cells engage with MHC II of macrophages to downregulate TLR pro-inflammatory signaling.

The secretory Candida effector Sce1 licenses fungal virulence by masking the immunogenicβ-1,3-glucan and promoting apoptosis of the host cells

Candida albicans deploys a variety of mechanisms such as morphological switch and elicitor release to promote virulence.However,the intricate interactions between the fungus and the host remain poorly understood,and a comprehensive inventory of fungal virulence factors has yet to be established.In this study,we identified a C.albicans secretory effector protein Sce1,whose induction and secretion are associated with vagina‐simulative conditions and chlamydospore formation.Sequence alignment showed that Sce1 belongs to a Pir family in C.albicans,which is conserved across several fungi and primarily characterized as aβ‐glucan binding protein in the Saccharomyces cerevisiae.Mechanically,Sce1 is primarily localized to the cell wall in a cleaved form as an alkali‐labileβ‐1,3‐glucan binding protein and plays a role in maskingβ‐glucan in acidic environments and chlamydospores,a feature that might underline C.albicans'ability to evade host immunity.Further,a cleaved short form of Sce1 protein could be released into extracellular compartments and presented in bone marrow‐derived macrophages infected with chlamydospores.This cleaved short form of Sce1 also demonstrated a unique ability to trigger the caspases‐8/9‐dependent apoptosis in various host cells.Correspondingly,genetic deletion of SCE1 led to dampened vaginal colonization of C.albicans and diminished fungal virulence during systemic infection.The discovery of Sce1 as a versatile virulence effector that executes at various compartments sheds light on the fungus–host interactions and C.albicans pathogenesis.

The regulation of host cytoskeleton during SARS-CoV-2 infection in the nervous system

The global economy and public health are currently under enormous pressure since the outbreak of COVID-19. Apart from respiratory discomfort, a subpopulation of COVID-19 patients exhibits neurological symptoms such as headache, myalgia, and loss of smell. Some have even shown encephalitis and necrotizing hemorrhagic encephalopathy. The cytoskeleton of nerve cells changes drastically in these pathologies, indicating that the cytoskeleton and its related proteins are closely related to the pathogenesis of nervous system diseases. In this review, we present the up-to-date association between host cytoskeleton and coronavirus infection in the context of the nervous system. We systematically summarize cytoskeleton-related pathogen-host interactions in both the peripheral and central nervous systems, hoping to contribute to the development of clinical treatment in COVID-19 patients.

National Epidemiology and Evolutionary History of Four Hand, Foot and Mouth Disease-Related Enteroviruses in China from 2008 to 2016

Hand, foot and mouth disease(HFMD) is a major public health concern in China. The most predominant enteroviruses that cause HFMD have traditionally been attributed to enterovirus A71(EVA71) and coxsackievirus A16(CVA16). Since its first large outbreak in 2008, the dominant HFMD pathogens are constantly changing. In 2013 and 2015, CVA6 exceeded both EVA71 and CVA16 to become the leading cause of HFMD in some provinces. However, there still lacks a comprehensive overview on the molecular epidemiology and evolution of HFMD-related enteroviruses at the national level. In this study, we performed systematic epidemiological analyses of HFMD-related enteroviruses using the data of 64 published papers that met the inclusion criteria, and conducted phylogenetic analyses based on 12,080 partial VP1 sequences identified in China before 31 st June 2018. We found that EVA71 prevalence has decreased sharply but other enteroviruses have increased rapidly from 2008 to 2016 and that one subtype of each enterovirus is represented during the epidemic. In addition, four genotypes EVA71_C4, CVA16_B1, CVA6_D and CVA10_C are the most predominant enterovirus strains and collectively they cause over 90% of all HFMD cases in China according to the phylogenetic trees using representative partial VP1 sequences. These four major enterovirus genotypes have different geographical distributions, and they may cocirculate with other genotypes and serotypes. These results suggest that more molecular epidemiological studies should be performed on several enteroviruses simultaneously, and such information should have implications for virological surveillance, disease management, vaccine development and policy-making on the prevention and control of HFMD.

Evolution of the novel coronavirus from the ongoing Wuhan outbreak and modeling of its spike protein for risk of human transmission

Dear Editor,The occurrence of concentrated pneumonia cases in Wuhan city,Hubei province of China was first reported on December 30,2019 by the Wuhan Municipal Health Commission(WHO,2020).The pneumonia cases were found to be linked to a large seafood and animal market in Wuhan,and measures for sanitation and disinfection were taken swiftly by the local government agency.The Centers for Disease Control and Prevention(CDC)and Chinese health authorities later determined and announced that a novel coronavirus(CoV),denoted as 2019-nCoV,had caused the pneumonia outbreak in Wuhan city(CDC,2020).Scientists from multiple groups had obtained the virus samples from hospitalized patients(Normile,2020).The isolated viruses were morphologically identical when observed under electron microscopy.

Negative regulation of NLRP3 infl ammasome signaling

Infl ammasomes are multiprotein complexes that serve as a platform for caspase-1 activation and interleukin-1β(IL-1β)maturation as well as pyroptosis.Though a number of infl ammasomes have been described,the NLRP3 inflammasome is the most extensively studied.NLRP3 inflammasome is triggered by a variety of stimuli,including infection,tissue damage and metabolic dysregulation,and then activated through an integrated cellular signal.Many regulatory mechanisms have been identifi ed to attenuate NLRP3 infl ammasome signaling at multiple steps.Here,we review the developments in the negative regulation of NLRP3 inflammasome that protect host from inflammatory damage.

The crucial roles of Th17-related cytokines/signal pathways in M. tuberculosis infection

Interleukin-17(IL-17),IL-21,IL-22 and IL-23 can be grouped as T helper 17(Th17)-related cytokines because they are either produced by Th17/Th22 cells or involved in their development.Here,we review Th17-related cytokines/Th17-like cells,networks/signals and their roles in immune responses or immunity against Mycobacterium tuberculosis(Mtb)infection.Published studies suggest that Th17-related cytokine pathways may be manipulated by Mtb microorganisms for their survival benefits in primary tuberculosis(TB).In addition,there is evidence that immune responses of the signal transducer and activator of transcription 3(STAT3)signal pathway and Th17-like T-cell subsets are dysregulated or destroyed in patients with TB.Furthermore,Mtb infection can impact upstream cytokines in the STAT3 pathway of Th17-like responses.Based on these findings,we discuss the need for future studies and the rationale for targeting Th17-related cytokines/signals as a potential adjunctive treatment.

The Role of Host Cytoskeleton in Flavivirus Infection

The family of flaviviruses is one of the most medically important groups of emerging arthropod-borne viruses. Host cell cytoskeletons have been reported to have close contact with flaviviruses during virus entry, intracellular transport, replication, and egress process, although many detailed mechanisms are still unclear. This article provides a brief overview of the function of the most prominent flaviviruses-induced or-hijacked cytoskeletal structures including actin, microtubules and intermediate filaments, mainly focus on infection by dengue virus, Zika virus and West Nile virus. We suggest that virus interaction with host cytoskeleton to be an interesting area of future research.

Type I interferons promote the survival and proinflammatory properties of transitional B cells in systemic lupus erythematosus patients

A hallmark of systemic lupus erythematosus(SLE)is the breaking of B-cell tolerance with the generation of high-affinity autoantibodies;however,the antibody-independent features of the B-cell compartment in SLE are less understood.In this study,we performed an extensive examination of B-cell subsets and their proinflammatory properties in a Chinese cohort of new-onset SLE patients.We observed that SLE patients exhibited an increased frequency of transitional B cells compared with healthy donors and rheumatoid arthritis patients.Plasma from SLE patients potently promoted the survival of transitional B cells in a type I IFN-dependent manner,which can be recapitulated by direct IFN-αtreatment.Furthermore,the effect of IFN-αon enhanced survival of transitional B cells was associated with NF-κB pathway activation and reduced expression of the pro-apoptotic molecule Bax.Transitional B cells from SLE patients harbored a higher capacity to produce proinflammatory cytokine IL-6,which was also linked to the overactivated type I IFN pathway.In addition,the frequency of IL-6-producing transitional B cells was positively correlated with disease activity in SLE patients,and these cells were significantly reduced after short-term standard therapies.Thus,the current study provides a direct link between type I IFN pathway overactivation and the abnormally high frequency and proinflammatory properties of transitional B cells in active SLE patients,which contributes to the understanding of the roles of type I IFNs and B cells in the pathogenesis of SLE.

Current understanding of Th2 cell differentiation and function

Helper T cell(Th)has been identified as a critical immune cell for regulating immune response since 1980s.The type 2 helper Tcell(Th2),characterized by the production of interleukin-4(IL-4),IL-5 and IL-13,plays a critical role in immune response against helminths invading cutaneous or mucosal sites.It also has a functional role in the pathophysiology of allergic diseases such as asthma and allergic diarrhea.Currently,most studies have shed light on Th2 cell function and behavior in specific diseases,such as asthma and helminthes inflammation,but not on Th2 cell itself and its differentiation.Based on different cytokines and specific behavior in recent research,Th2 cell is also regarded as new subtypes of T cell,such as IL-9 secreting T cell(Th9)and CXCR5+T follicular helper cells.Here,we will discuss the latest view of Th2 cell towards their function and the involvement of Th2 cell in diseases.

Celastrol specifically inhibits the activation of NLRP3 inflammasome

Dear Editor,Inflammasomes are vital components of the innate immune system that survey microbial infections or sterile challenges in the cytosol(de Zoete et al.,2014).A typical inflammasome is composed of a sensor protein such as NOD like receptor(NLR)or AIM2 like receptor(ALR),the